US8478395B2 - Method of measuring electrical resistance value of corneal trans-epithelium - Google Patents
Method of measuring electrical resistance value of corneal trans-epithelium Download PDFInfo
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- US8478395B2 US8478395B2 US12/921,069 US92106909A US8478395B2 US 8478395 B2 US8478395 B2 US 8478395B2 US 92106909 A US92106909 A US 92106909A US 8478395 B2 US8478395 B2 US 8478395B2
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- cornea
- insulator
- electric resistance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
- A61B5/053—Measuring electrical impedance or conductance of a portion of the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/6813—Specially adapted to be attached to a specific body part
- A61B5/6814—Head
- A61B5/6821—Eye
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
- A61B2562/0215—Silver or silver chloride containing
Definitions
- the present invention relates to a method for measuring a corneal transepithelial electric resistance value, which is less invasive to respective tissues of eyes including a corneal epithelium.
- a cornea is a transparent membrane with a thickness of about 0.5 mm, and has a five-layer structure which consists of corneal epithelial cells, a Bowman membrane, corneal stroma, a Descemet's membrane and corneal endothelial cells, in this order from the surface of body.
- corneal epithelial cells have high regenerating capability, a serious corneal ulcer might occur, or a nonreversible corneal opacity might be left, in the case where a disorder of the epithelial cells is serious. Therefore, there have been strong demands for measuring the degree of the disorder of the corneal epithelium quantitatively and carrying out a proper treatment in an earlier stage.
- the conventional method for measuring the degree of a disorder of the cornea mainly depends on a visual inspection method, it is difficult to quantitate the disorder of the corneal epithelium, and there has been a demand for a method for representing the degree of the disorder of the cornea by a numeric value and for quantitating the degree of the disorder thereof.
- TER corneal transepithelial electric resistance
- the present inventors at first carried out experiments in which a cut-out cornea was fixed on a Ussing chamber by which an accurate TER can be determined by using a short-circuit current method, with the value of the area (a) being constant; however, since the cut-out cornea is different in its state from that in a living body, the experiments failed to reflect a true biological reaction. Therefore, the present inventors have found a method in which electrode needles are placed on the corneal epithelium and in the anterior chamber of a living eye and an electric resistance is measured by flowing an electric current therebetween (see Non-Patent Document 4). In this case, the measurement of TER is performed for a living cornea by using the principle of the Ussing chamber, and an accurate TER can be determined when the value of the measurement area (a) is constant.
- this method is an invasive method that is accompanied by an anterior chamber centesis, it is not possible to apply this method to human, and this method is not suitable for diagnosis and treatment of a corneal disorder in the clinical field.
- Non-Patent Document 5 has disclosed a method for measuring a corneal resistance value about a living eye by using corneal contact lens (CL) provided with electrodes. Since this method is not invasive to respective portions of the eye, it may be applicable to human.
- CL corneal contact lens
- Non-Patent document 5 has a problem with the detection sensitivity.
- Patent Document 1 has disclosed a device for detecting a damage and the like of the corneal epithelium, and this device measures a reduction in a potential difference between a cornea and a sclera as an index for the damage.
- the Ic and the Vs need to be measured with high precision; however, in an actual operation, the current Ic generated from the corneal endothelium is very weak and is not constant. Since the scleral electric potential Vs varies depending on measuring conditions and individuals, it is not possible to determine a corneal disorder accurately when compared with this.
- Patent Document 1 roughly observes the electrophysiological phenomenon that the electric resistance value is lowered upon occurrence of a corneal disorder, its measuring principle and accuracy are far behind the technique of the present application.
- An object of the present invention is to provide an evaluation method of a corneal disorder that can measure a disorder of a cornea quantitatively and is applicable to living eyes. Specifically, the object is to provide a measuring method for measuring a corneal transepithelial electric resistance value, in which a corneal TER can be measured with superior sensitivity, and which is applicable to the living eyes.
- the present inventors have found that by placing one of electrodes on the cornea with the other electrode being placed on the conjunctiva, it becomes possible to provide a method that is less invasive to the eyes in comparison with a conventional method that inserts one of the electrodes into the anterior chamber, and also to obtain results of measurements that are equivalent to the conventional method.
- Im and a are always constant, and since ⁇ Vc can be accurately measured, the corneal disorder can be accurately evaluated by using the TER.
- the present inventors have successfully manufactured a novel measuring device that is suitable to an implementation of the method, which resulted in the completion of the present invention.
- the present invention provides:
- a method for measuring a corneal transepithelial electric resistance comprising placing electrodes on a cornea and a conjunctiva;
- a device for measuring a corneal transepithelial electric resistance about a living eye which comprises:
- an electric resistance value of human corneal epithelial cells can be measured even for living eyes.
- the method of the present invention provides a simpler method which can obtain results of measurements that are equivalent to a method that uses the anterior chamber centesis.
- a corneal transepithelial electric resistance value of the present invention By utilizing the method for measuring a corneal transepithelial electric resistance value of the present invention, it becomes possible to quantitatively detect a corneal disorder of the living eyes, without the necessity of the anterior chamber centesis. It can be used for a diagnosis of corneal disorder so as to utilize the detection data obtained thereby for an early treatment.
- the method for measuring a corneal transepithelial electric resistance value of the present invention makes it possible to perform continuous measurements in a short period of time, and is useful for the research for drug screening (for example, pre-clinical studies and the like), the research for evaluating efficacy of drugs, the research for evaluating the corneal toxicity of a drug, and so on.
- the method for measuring a corneal transepithelial electric resistance value of the present invention makes it possible to measure a barrier function of a living cornea, which has been impossible by the conventional method.
- a barrier function of a living cornea which has been impossible by the conventional method.
- FIG. 1 is a schematic drawing that shows one embodiment of the present invention.
- a corneal electrode is disposed in a conductor (buffer solution) which fills the inside of an insulator.
- a conjunctival electrode is in contact with a lacrimal fluid reserved in a conjunctival-sac.
- FIG. 2 is a schematic drawing that shows another embodiment of the present invention.
- a corneal electrode of an applanation tonometer type (with conductor (gel) inside an insulator) is used, and a conjunctival electrode is covered with the conductor (gel).
- FIG. 3 is a schematic drawing that shows still another embodiment of the present invention.
- An electrode of a contact lens type which is equipped with a corneal electrode, a conductor (gel), an insulator and a conjunctival electrode, is used.
- FIG. 4 is a graph that shows measured values of TER after administration of a 0.02% BAC.
- the axis of ordinates shows ⁇ cm 2 and the axis of abscissas indicates seconds that have been elapsed after the administration of the BAC.
- FIG. 5 shows the results of the same measurements as of FIG. 4 , when the measured TER value prior to the administration is 100%.
- the axis of ordinates indicates % and the axis of abscissas indicates seconds that have been elapsed after the administration of the BAC.
- FIG. 6 is a schematic drawing that shows a particularly preferable TER measuring device of the present invention.
- a corneal contact surface of an insulator has a curvature that is the same as that of the cornea and a conjunctival electrode portion is formed into a sheet shape.
- FIG. 7 shows a record of TER of a normal cornea before and after the administration of a 0.02% BAC to the cornea, measured by the measuring device of FIG. 6 .
- the TER value became a stable value within 1 second, after the measuring device had been contacted with the cornea.
- the present invention provides a method for measuring a corneal transepithelial electric resistance, comprising placing electrodes on a cornea and a conjunctiva (referred to as the method of the present invention).
- the method of the present invention comprises:
- corneal transepithelial electric resistance means “transepithelial electric resistance: TER” of “cornea”.
- the TER reflects the barrier function of the epithelium. It has been known that as the measured TER is lower, the disorder degree of the epithelial cell is higher. That is, by measuring a corneal transepithelial electric resistance, the barrier function of the corneal epithelium can be evaluated so that the disorder degree of the corneal epithelial cell can also be evaluated.
- the “barrier function” means a function of controlling various substances that move into and out of the body through the epithelium, which is acquired by the forming of junctions peculiar to the epithelial cell, such as an occluding junction (tight junction) and an anchoring junction (adherens junction, desmosome, and the like) among the epithelial cells.
- the value of the corneal transepithelial electric resistance of, for example, is about 100 to 700 ⁇ cm 2 for rabbit, when measured by using a conventional method with an isolated corneal piece (cut-out corneal piece).
- a TER value that is slightly higher than this can be obtained.
- the normal value of the corneal transepithelial electric resistance of the rabbit is about 500 to 1500 ⁇ cm 2 .
- the reduction of the corneal transepithelial electric resistance (corneal TER) value serving as an index of a degree of disorder of the cornea is considered to be a result of a rise of the substance permeability of the cornea due to a disorder (referred to also as an injury) of the corneal epithelial cells, that is, a reduction of the barrier function.
- the corneal epithelium Since the corneal epithelium is located at the outermost portion of the cornea and contacts with the outer environment, it is a portion that is easily subjected to a disorder.
- the disorder of the cornea, the disorder of the corneal epithelium and the disorder of the corneal epithelial cells are terms that are used interchangeably.
- the disorders of the corneal epithelial cells refer to as various disorders causing damages to junctions, such as an occluding junction (tight junction) and an anchoring junction (adherens junction, desmosome, and the like) among the corneal epithelial cells, and for example, the disorders include a corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema), a corneal infection (bacterial corneal ulcer, keratomycosis, viral keratitis, and so on).
- disorders of the corneal epithelial cells may be caused by a trauma, an inflammatory reaction, ultraviolet rays, hypoxia, dry eyes, improper wear of contact lens, foreign substances such as dusts, chemicals and agents (for example, an antiseptic contained in eye drops) and the like.
- the disorders of the corneal epithelial cells may lead microorganism infection into the eyes, an ulcer, low vision and the like.
- the corneal epithelial cells can be regenerated; however, when there is a serious disorder to the corneal epithelial cells, it will affect adversely a group of cells inside thereof (collectively referred to as corneal endothelial cells in the present specification). Since the regenerating capability of the corneal endothelial cells is lower than that of the corneal epithelial cells, the disorder of the corneal epithelial cells is preferably treated in an earlier stage. For this purpose, it is preferable that the disorder of the corneal epithelial cells needs to be detected earlier.
- the corneal disorder is induced by using benzalkonium chloride (BAC) generally used as an antiseptic in eye drops and the like; however, it is clear that the method of the present invention can be applicable to a detection of any corneal disorder caused by any of the above-mentioned reasons.
- BAC benzalkonium chloride
- the degree of disorder of the cornea means a degree of disorder of the corneal epithelium, and it is represented qualitatively as a percentage % of a TER value after subjected to a corneal disorder relative to the normal value without any corneal disorder.
- electrodes to be used for the measurements are respectively placed on the cornea and on the conjunctiva.
- the conjunctiva is composed of a bulbar-conjunctiva, a conjunctival formices and a palpebral-conjunctiva.
- the conjunctiva includes any of membranes forming the conjunctiva.
- a space formed by these conjunctiva a sac-like structure of conjunctiva centered on the conjunctival formices is referred to as “the conjunctival-sac”.
- the expression “placing an electrode on the cornea” means that an electrode is disposed at a position in contact with the outer surface of the corneal epithelium directly or indirectly via a conductor.
- the expression “placing an electrode on the conjunctiva” means that the electrode is disposed in the conjunctival-sac at a position in contact with the outer surface of the bulbar-conjunctiva, conjunctival formices or palpebral-conjunctiva, or at a position in contact with any of the above conjunctivas via a conductor.
- Electrodes to be placed on the cornea and the conjunctiva can be a positive electrode or a negative electrode so long as at least one positive electrode and at least one negative electrode are placed on the cornea and the conjunctiva, respectively.
- the number of the electrodes to be used is not particularly limited, and the number may be determined by the person skilled in the art as necessary.
- the kinds of electrodes to be used are not particularly limited as long as the objective and effects of the present invention can be achieved, and any electrodes known per se for measuring the transepithelial electric resistance may be utilized as necessary.
- materials for the electrode include gold, platinum, silver, silver chloride, copper, stainless steel, iron, carbon and the like.
- the electrode of gold, platinum, silver, or silver chloride is used from a viewpoint of being less harmful to a living body.
- any electrodes known per se used for the living body may be used as necessary, as long as the objective and effect of the present invention can be achieved without giving any disorder to the tissue of the eyes.
- electrodes having various shapes such as a rod shape, a plate shape, a disc shape and a ring shape, made of the above-mentioned electrode materials, may be proposed without limitation.
- the electrode may be directly contacted with the cornea or the conjunctiva without a conductor, or may be used together with the conductor.
- the conductor is placed at a gap portion between the electrode and the cornea or the conjunctiva.
- any materials known per se as a conductor material may be used as necessary.
- the conductor may be solid, liquid, gel and the like, and from the viewpoint of closely contacting the electrode more flexibly with the cornea and/or conjunctiva, liquid or gel is preferably used.
- the conductor includes physiological saline, buffer solution (for example, a phosphate buffer solution, Hanks' Balanced Salt Solution, and the like) and hydrogel (for example, a gel of hyaluronic acid or atelocollagen, and the like), but not limited thereto.
- buffer solution for example, a phosphate buffer solution, Hanks' Balanced Salt Solution, and the like
- hydrogel for example, a gel of hyaluronic acid or atelocollagen, and the like
- the conductor may be substituted with a lacrimal fluid reserved in the conjunctival-sac.
- the contact surface to the cornea or conjunctiva of the conductor is desirably formed into a shape adapted to the shape of the outer surface of the cornea or the conjunctiva so as to be contacted with the cornea or the conjunctiva as closely as possible (for example, when used for the corneal electrode, the contact surface to the cornea has the same curvature as that of the cornea).
- the measuring method of the present invention measures corneal transepithelial electric resistance by flowing an electric current through the corneal epithelium, the electric current needs to surely pass through the corneal epithelium. Since a lacrimal fluid normally exists on the cornea, the electric current flows through not only the corneal epithelium, but also the lacrimal fluid, in the case where the electrode is simply placed on the cornea, with the result that there is a possibility of a failure to obtain a accurate corneal transepithelial electric resistance value.
- an insulator is preferably disposed around a periphery of the cornea electrode (in the case where a conductor is interposed between the electrode and the cornea, around a periphery of the conductor).
- any substance known per se may be used as an insulating substance as necessary, as long as it can achieve the objective and effect of the present invention without giving any adverse effect to the eyes, and a nitrile rubber, a silicone rubber, such as polydimethylsiloxane (PDMS), and the like may be proposed without limitation.
- a plurality of insulators may be combined, and used as necessary.
- the insulator is provided in a form integrated with the corneal electrode.
- the expression that the insulator and the corneal electrode are “integrated” means that the insulator and the corneal electrode are pre-arranged in such a manner that the placement of the insulator and the placement of the corneal electrode need not be carried out separately, and examples of such arrangements include an arrangement in which the insulator and the corneal electrode are directly contacted with each other to form an integrated shape, and an arrangement in which another substance, such as a conductor, is interposed between the insulator and the corneal electrode to form an integrated shape as a whole, but not limited thereto.
- the shape of the insulator may vary depending on the shapes of the electrode, the conductor and the like to be used; however, the shape is not particularly limited, as long as it is placed around the periphery of the electrode or the conductor so as to prevent the short circuit of the electric current from the electrode or the conductor to the lacrimal fluid and the like, and has a shape capable of closely contacting with the cornea.
- a ring shape, a cylindrical shape and the like are proposed as the shape of the insulator.
- a dimension of the ring may be selected as necessary within a range in which its diameter (at least an inner diameter) does not exceed a diameter of the cornea.
- an inner diameter of the ring is preferably 3 to 9 mm (for example, about 6 mm).
- an inner diameter of the ring is 3 to 11 mm (for example, about 7 mm).
- Methods for closely contacting the insulator thereto include a method using a light pressing, a suction by a negative pressure, an insulator gel, adhesive, eye ointment, etc., and those that give no damages or disorders to the cornea and the other eye tissues are preferably used.
- the method using a light pressing, the insulator gel or eye ointment is preferably used, and the insulator gel and the eye ointment are particularly preferable.
- the insulator gel although not particularly limited, petrolatum and the like may be used.
- cyanoacrylate type adhesive acrylic resin type adhesive and the like are proposed, without limitation.
- acrylic resin type adhesive acrylic resin type adhesive and the like are proposed, without limitation.
- eye ointment Tarivid eye ointment (registered trademark), Flavitan ophthalmic ointment (registered trademark) and so on are proposed, without limitation.
- the electric current to be flowed between the electrodes is not particularly limited, as long as the TER value can be measured without causing any damage to the epithelial cells, and it is preferably 10 ⁇ A to 10 mA, more preferably 20 ⁇ A to 100 ⁇ A.
- the electric current may be either a DC current or an AC current.
- a measuring device for measuring an electric resistance a short-circuit current device, a voltage-electric resistance value measuring device (for example, EVOM (registered trademark, from World Precision Instruments, Inc.)) and the like may be used, without limitation.
- EVOM registered trademark, from World Precision Instruments, Inc.
- the TER value is expressed by ⁇ cm 2 , and obtained by multiplying the resulting electric resistance value by an area (a) where the current is passed through.
- the area (a) corresponds to an area of the cornea inside the insulator that is placed around the corneal electrode.
- the expression “living eye” means an eye that has not been taken out of the living animals exemplified below as the subject for the application of the present invention.
- the living eye means an eye that has not been subjected to an invasive operation, such as an extraction, incision, and the like.
- Examples of the subject for the application of the method of the present invention include: mammals such as human, experimental animals, pet animals and domestic animals (for example, rabbits, rats, mice, hamsters, cats, dogs, cows, swine, horses, sheep, monkeys, and the like).
- mammals such as human, experimental animals, pet animals and domestic animals (for example, rabbits, rats, mice, hamsters, cats, dogs, cows, swine, horses, sheep, monkeys, and the like).
- the method of the present invention is intended to be applied to those experimental animals for use in the preclinical study of eyedrop and the like and animals whose treatment for corneal disorder is desired.
- the mammal is preferably human.
- the present invention also provides a device for measuring a corneal transepithelial electric resistance of a living eye (referred to as the device of the present invention), and this device comprises (1) a first electrode suitable to be placed on a cornea, (2) a second electrode suitable to be placed on a conjunctiva, and (3) an insulator that is integrated with the first electrode.
- the device of the present invention comprises (1) a first electrode suitable to be placed on a cornea, (2) a second electrode suitable to be placed on a conjunctiva, and (3) an insulator that is integrated with the first electrode.
- the respective components of this device are as above-mentioned.
- the corneal electrode As the first electrode, the corneal electrode, described in detail in the above-mentioned method of the present invention, is preferably used.
- the second electrode As the conjunctival electrode, described in detail in the above-mentioned method of the present invention, is preferably used.
- the insulator As the insulator, the aforementioned insulator described in detail in the method of the present invention, is preferably used.
- the device of the present invention is characterized in that the corneal electrode and the insulator are integrated. In this case, the expression “integrated” is used as the same meaning as that explained before.
- the integrated corneal electrode and the insulator is hereinafter referred to as a “corneal electrode portion”.
- the corneal electrode portion may consist of only the electrode and the insulator, or may further include a member for connecting the electrode with the cornea.
- the corneal electrode portion may further include a conductor for contacting the electrode indirectly with the cornea as another component. That is, in a preferred embodiment, the corneal electrode portion has a corneal electrode integrated with the insulator via the conductor.
- a solid or gel-like material may be selected for maintaining integrity of the corneal electrode portion.
- a material such as hydrogel (for example, a gel of hyaluronic acid, atelocollagen, and the like), is particularly preferable.
- the shape of the corneal electrode itself is not particularly limited, as long as it can be kept inside the insulator around the corneal electrode, and any electrode known per se as an electrode for measuring a transepithelial electric resistance, and the like, may be used as necessary.
- any electrode known per se as an electrode for measuring a transepithelial electric resistance, and the like may be used as necessary.
- various shapes such as a rod shape, a plate shape, a linear shape and the like, are proposed, although not intended to be limited thereto.
- any shape may be used as a shape of the corneal electrode portion, as long as it can make close contact with the cornea, and specific examples thereof include a circular cylinder shape, a rectangular cylinder shape, and the like, with a concave portion as a contact surface to the cornea; however, not particularly limited thereto; as a shape of the corneal electrode portion, for example, an applanation tonometer-like shape and a contact lens-like shape may also be used.
- the size of the corneal electrode portion may be of any size as long as an inner diameter of the insulator does not exceed a diameter of the cornea, and in the case of human, an inner diameter of the insulator is preferably up to the corneal diameter (about 12 mm), and preferably 1-12 mm.
- An electrode alone may form a conjunctival electrode, or a conjunctival electrode and a solid or gel-like conductor may be integrated (inclusively referred to as a “conjunctival electrode portion”).
- the size of the conjunctival electrode portion may be a size that the entire conjunctival electrode portion can be kept in the conjunctival-sac; however, it is sufficient that at least one portion of the conjunctival electrode portion can be made in contact with the conjunctiva or a lacrimal fluid reserved in the conjunctival-sac.
- the size is preferably within a range of 1-10 mm as a whole, in the case of human.
- a shape thereof may be any shape as long as it allows the conjunctival electrode portion to be contacted with a conjunctiva or a lacrimal fluid reserved in a conjunctival-sac, and preferably, a shape without giving disorders to the tissues of the eyes.
- examples thereof include, but not limited to, a flat shape, a plate shape, a linear shape, a sheet shape, and the like, with its conjunctival contact surface being concave.
- the corneal electrode portion and the conjunctival electrode portion are integrated in such a mode as to prevent an electric current from flowing directly therebetween.
- FIGS. 1 to 3 are schematic drawings (sagittal plane) that exemplify possible embodiments of the present invention. However, illustrated embodiments are exemplary only.
- FIG. 1 shows an example of a corneal electrode that uses a ring-shaped insulator and a buffer solution.
- FIG. 2 shows an example of a corneal electrode of an applanation tonometer type
- FIG. 3 shows an example of a contact lens-type electrode. In FIG. 3 , the conjunctival electrode is attached to an edge portion of a contact lens.
- any material generally used for the contact lens may be used as the material constituting the external portion of the insulator, and for example, plastic materials (for example, acrylic resin, polycarbonate, and the like), rubbers and the like may be used, although not particularly limited thereto.
- FIG. 6 is a schematic drawing that shows one example of a particularly preferred embodiment of the present invention.
- the corneal electrode, the insulator, the conductor and the conjunctival electrode are integrated, immediate measurement of TER is readily possible only by contacting this system with the living eyes, which consequently eliminates time-consuming setting processes; thus, it presents to the reduction of stress on a subject.
- silicone rubber nitrile rubber and the like may be used as the insulator.
- the silicone rubber include: polydimethylsiloxane (PDMS), vinyl methyl silicone rubber and the like may be proposed, without limitation.
- PDMS polydimethylsiloxane
- the silicone rubber is particularly preferable as a highly safe material because of its high biocompatibility and softness, which causes scratches on the corneal surface, and further it is an easily processible material. By using the silicone rubber as the insulator, it is possible to prevent corneal abrasion caused by the measuring device.
- the insulator is preferably a ring shape or a cylindrical shape (for example, inner diameter: 1 to 13 mm (for example, 3 to 11 mm), thickness: 0.1 to 5 mm (for example, 1 to 3 mm), and height: 0.1 to 20 mm (for example, 1 to 10 mm)), and its contact surface to the cornea has the same curvature as that of the cornea.
- the expression “the same curvature as that of the cornea” means that the contact surface has the same curvature or substantially the same curvature as that of the cornea, as long as the close contact between the insulator and the cornea is ensured, that is, the contact surface does not necessarily have the perfectly same curvature as that of the cornea.
- the thickness at the contact surface may be greater than the above-mentioned thickness.
- the curvature of the cornea can be measured by a general method using an ophthalmometer, a keratometer, a photokeratoscope, and the like, and the curvature to be applied to the insulator may be altered depending on kinds and the like of a subject as necessary.
- the curvature radius is 650 to 850 mm (for example, 790 mm).
- the curvature radius is 600 to 800 mm (for example, 750 mm).
- the entire peripheral portion of the insulator is surely contacted with the cornea by a light pressing and the like so as not to leave any lacrimal layer between the insulator and the eye surface.
- the insulator is desirably made to have a certain thickness (preferably, 1 to 3 mm) so that, even when the lacrimal fluid layer is left, only less electric current can pass through the lacrimal fluid layer, that is, the value of electric resistance over the lacrimal fluid layer becomes greater so that the value of electric resistance over the epithelium can be ignored. Any insulating method may be used as long as the insulation is positively achieved.
- a conductor gel is disposed inside this insulator (for example, see FIGS. 2 and 6 ).
- the conductor gel for example, gels of synthetic macromolecules, such as polyethylene glycol containing a buffer solution, and gels of biological macromolecules, such as hyaluronic acid, atelocollagen, gelatin, cellulose and agarose, may be used. It is preferable to use the gel of hyaluronic acid and atelocollagen, because they are superior in biocompatibility and highly safe materials with a conductive property, and easily processed; however, a material of the gel is not limited thereto, as long as it meets these conditions.
- the corneal contact surface of the conductor gel has the same curvature as that of the cornea, in order to be closely contacted with the cornea.
- the corneal electrode is disposed so as to be contacted with the conductor gel, or embedded into the conductor gel so that the corneal electrode and the insulator can be integrated (corneal electrode portion).
- the corneal electrode is indirectly contacted with the cornea via the conductor gel.
- the corneal electrode to be used is miniaturized one adapted to the present embodiment.
- the size/shape/material and the like of the corneal electrode are the same as those described earlier.
- an outside shape of a portion including the corneal electrode portion, as a whole is not particularly limited, and may be altered as necessary depending on modes of use, and determined appropriately by taking into consideration, for example, easiness in handling, installation into a usual ophthalmology medical device (such as a slit-lamp and an ophathalmotonometry receptacle), and the like; as an example, a shape as shown in FIG. 6 is proposed.
- the outside shape of the portion including the corneal electrode portion, as a whole may be formed into a shape that can be grabbed by the hand and operated (for example, a pen shape), without limitation.
- the above-mentioned insulator itself may constitutes the outer layer that forms the outer shape, or the corneal electrode portion (in this context, with the conductor also included) may be integrated with another member that forms the outside shape as above.
- the conjunctival electrode portion is formed into a sheet shape.
- the sheet shape means a shape having, for example, a thickness in a range from 0.001 cm to 0.1 cm, a length (b in FIG. 6 ) in a range from 0.5 cm to 5 cm, and a width (a in FIG. 6 ) in a range from 0.1 cm to 2 cm, and a preferable example is a sheet having a thickness of 0.01 cm, a length of 1 cm and a width of 0.5 cm.
- a sheet having any shape, such as a rectangular shape, a round shape, and an elliptical shape, may be used; however, a sheet having an approximately rectangular shape is preferably used.
- a shape with rounded corners may be also used.
- the conjunctival electrode By forming the conjunctival electrode into a sheet shape, its insertion into the conjunctival-sac can be easily carried out.
- This sheet can be made from, for example, a material, such as PET, polyimide, silicone rubber and acrylic material, and, from viewpoints of high strength, high flexibility and easiness in molding, PET and polyimide are preferably used.
- the conjunctival electrode is preferably disposed at a distal end (on an opposite side to the attachment point to the corneal electrode portion) of the sheet-shaped conjunctival electrode portion; however, it may be disposed at any position, as long as the direct contact with the conjunctiva or the lacrimal fluid reserved in the conjunctival-sac, or the indirect contact therewith via a conductor can be ensured, and for example, it may be disposed at a position within 5 mm from the distal end of the conjunctival electrode portion.
- the conjunctival electrode portion may be formed into a shape covered with a conductor, wherein the aforementioned hydrogel may be used as the conductor, however, not particularly limited to this, any gel may be used as long as it has a conductive property.
- the conjunctival electrode is preferably disposed on the conjunctival contact side of the sheet; however, in the case where the conductor is used, it may be disposed on the outer side (on the side opposite to the conjunctival contact surface) of the sheet, or may be embedded into the conductor.
- the conjunctival electrode is held on the conjunctiva, or inside the conjunctival-sac, or inside the lacrimal fluid, and the position is at 0.1 to 15 mm from the corneal limbus, and is desirably at 3 mm therefrom.
- the conjunctival electrode portion is attached to the corneal electrode portion with an angle according to a shape of the eyeball, so as to be appropriately placed when the present device is contacted with the conjunctiva.
- the corneal electrode portion and the conjunctival electrode portion may be altered as necessary depending on the sizes of the cornea and eyeball of the subject. For example, in the case of human infant, human child, mouse, rat, monkey and so on, the size may be made smaller, while in the case of large-size animals, such as swine and cow, the size may be made larger.
- the present invention further provides a drug screening system which is characterized in that the above-mentioned method of the present invention is used, or in that the device of the present invention is involved as a component. Since the application of the method of the present invention and the device of the present invention makes it possible to quantitatively measure a corneal disorder of the living eyes, it is possible to carry out a screening for candidate compounds of a therapeutic agent for diseases causing disorders to the cornea (such as, for example, corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema) and a corneal infection (such as bacterial-corneal ulcer, keratomycosis, viral keratitis and the like)) by using the model animal with an induced corneal disorder.
- a therapeutic agent for diseases causing disorders to the cornea such as, for example, corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema)
- TER measurements are carried out about the living cornea, and those test compounds whose administrations have significantly improved the TER value can be selected as candidate compounds for the therapeutic agent of the disease causing the disorder of the cornea.
- the present invention further provides an efficacy and/or toxicity evaluation system for drugs which is characterized in that the above-mentioned method of the present invention is used, or in that the device of the present invention is involved as a component. Since the application of the method and device of the present invention and the device of the present invention makes it possible to quantitatively measure the corneal disorder of the living eye, it is possible to evaluate an efficacy of a therapeutic agent for diseases causing disorders to the corneal (such as, for example, corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema) and a corneal infection (such as bacterial corneal ulcer, keratomycosis, viral keratitis and the like)), for example, by using an experimental animal with a corneal disorder or a human who is suffering from a disease causing a corneal disorder, as a subject.
- a therapeutic agent for diseases causing disorders such as, for example, corneal erosion, a corneal ulcer
- TER measurements are carried out about the living cornea of the subject, and in the case where the TER value is significantly improved by the administration of the drug, it is possible to determine that the drug is effective for treatment of the disease causing the disorder of the cornea.
- the drug is effective for treatment of the disease causing the disorder of the cornea.
- an experimental animal or a human that is suffering from a disease of the eye other than the corneal disorder as a subject, it is possible to evaluate toxicity to the cornea of a therapeutic agent for the disease.
- TER measurements are carried out about the living cornea of the subject, and in the case where the TER value is significantly worsened by the administration of the drug, it is possible to determine that the drug has toxicity to the cornea.
- the present invention also provides a diagnosis agent for a disease causing a disorder of the cornea (for example, corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema) and a corneal infection (such as bacterial corneal ulcer, keratomycosis, viral keratitis and the like)) that contains a pharmaceutically acceptable substance that can be used as a conductor or used for closely contacting an insulator with the cornea in the method of the present invention.
- a disorder of the cornea for example, corneal erosion, a corneal ulcer, a corneal perforation, a corneal edema (epithelial edema) and a corneal infection (such as bacterial corneal ulcer, keratomycosis, viral keratitis and the like)
- a pharmaceutically acceptable substance that can be used as a conductor or used for closely contacting an insulator with the cornea in the method of the present invention.
- Examples of the pharmaceutically acceptable substance that can be used as a conductor include: physiological saline, a buffer solution (for example, a phosphate buffer solution and Hanks' Balanced Salt Solution and the like), as well as hydrogel and so on.
- Examples of the pharmaceutically acceptable substance that can be used for closely contacting an insulator with the cornea include an insulator gel, an adhesive, and an eye ointment.
- the insulator gel petrolatum and the like may be used, as the adhesive, cyanoacrylate-type adhesive, acrylic resin-type adhesive and the like may be used, and as the eye ointment, Tarivid eye ointment (registered trademark), Flavitan ophthalmic ointment (registered trademark) and so on are proposed, without limitation.
- the diagnosis agent of the present invention may further contain the other pharmaceutically acceptable additives, such as an antiseptic, an isotonizing agent, a pH adjusting agent and a stabilizer.
- the diagnosis of a disease causing a corneal disorder by the use of the diagnosis agent of the present invention is performed by carrying out the above mentioned method of the present invention with the diagnosis agent used as a means for closely contacting the conductor or the insulator with the cornea to measure TER about the living cornea of the subject, and then by comparing the measured value with a normal value.
- Electrodes were placed on a cornea and into an anterior chamber of a rabbit, and after administration of 0.02% BAC, a corneal TER was measured.
- Silver-silver chloride electrode having a rod shape was placed on a cornea and into a conjunctival sac of a living rabbit, and a 0.02% BAC was administered thereto.
- a change in the corneal TER due to exposure to BAC was measured by a voltage-electric resistance value measuring device.
- a rubber ring (6 mm in the inner diameter) was fixed onto the cornea around the periphery of the electrode by using a bioadhesive (Aron alpha A from Sankyo Co., Ltd.) for insulation, so that an electric current is surely passed through the epithelium of the cornea.
- FIGS. 4 and 5 show the comparisons of results obtained from comparative example 1 and example 1.
- the TER reduction curve obtained by the conjunctival-sac method was similar to the TER reduction curve obtained by the conventional anterior chamber centesis method. Setting the TER before the administration of the BAC to 100%, the TER at ten seconds after the administration was 35.1 ⁇ 6.8%, and after a lapse of 60 seconds, it was significantly reduced to 13.5 ⁇ 2.1% (p ⁇ 0.01). In the anterior chamber centesis method, 60 seconds after the administration, the TER was 19.7 ⁇ 5.9%. The TER value after a lapse of 60 seconds was 175 ⁇ 14 ⁇ cm 2 in the conjunctival-sac method, and 138 ⁇ 10 ⁇ cm 2 in the anterior chamber centesis method.
- the method of the present invention makes it possible to obtain detection results comparable to those of the anterior chamber centesis method.
- a silver electrode and a silver-silver chloride electrode having a diameter of 1 mm were placed on a round cover glass having a diameter of 12 mm.
- PDMS having a circular cylinder shape with 10 mm in diameter and 6 mm in inner diameter and having a curvature radius of the corneal contact surface of 7.9 mm was secured onto the cover glass by using an adhesive.
- An Eppendorf tube was attached to a rear side (on the side opposite to the corneal contact surface (cover glass side)) for mount onto a slit-lamp.
- the inner space of the PDMS was filled with an atelocollagen gel and its curvature radius was adjusted to 7.9 mm.
- a silver electrode and a silver chloride electrode having a diameter of 1 mm were placed on a PET sheet of 0.005 ⁇ 0.5 ⁇ 1 cm, at position of 1 mm from the distal end of the sheet on the eyeball side.
- the PET sheet, the silver electrode and the silver chloride electrode were thinly coated with a collagen gel.
- This conjunctival electrode portion was secured to the Eppendorf tube of the corneal electrode portion with an angle according to a shape of the eyeball by using an adhesive.
- TER measuring device By using thus prepared TER measuring device, a change in the corneal TER of a living rabbit was measured.
- a Japanese white rabbit was put under general anesthesia and the eyes were kept open by using adhesive tapes.
- the above-mentioned device is attached to the tip of the slit-lamp, the corneal electrode portion was correctly contacted with a center portion of the cornea and the conjunctival electrode portion was contacted with the conjunctival-sac and the lacrimal fluid reserved therein, by operating the slit-lamp.
- FIGS. 7 and 8 show the results.
- FIG. 7 shows that immediately after the TER measuring device has been contacted with the cornea, a TER can be measured.
- a stable TER value Prior to the BAC administration (indicated as “normal cornea” in FIG. 7 ) as well as after the BAC administration, within one second after the device was contacted with the cornea, a stable TER value could be measured.
- FIG. 8 one minute after the BAC administration, the TER was significantly reduced. This value was consistent with the results shown in FIG. 4 .
- the present invention provides a detection method for a corneal disorder that is less invasive to the living eye. Since the detection method according to the present invention requires no anterior chamber centesis, it is applicable even to human, and can be utilized for diagnosis and earlier treatment of a corneal disorder. Moreover, the method of the present invention makes it possible to carry out measurements within a short period of time after a corneal disorder and also to carry out over time measurements of a corneal disorder, and is useful for studies for drug screening, studies for evaluating efficacy of drugs, studies for evaluating influences of a drug to the eyes, and the like. Moreover, by using the method of the present invention, it becomes possible to obtain useful new findings with respect to corneal barrier functions in various corneal diseases, and consequently to contribute greatly to developments of the ophthalmology and ophthalmic medicine.
Abstract
Description
- patent document 1: JP-Y-S48-10716
- non-patent document 1: Rojanasakul Y. et al., Int. J. Pharm., (66) 131-142 (1990)
- non-patent document 2: Rojanasakul Y. et al., Int. J. Pharm., (63)1-16 (1990)
- non-patent document 3: Chetoni P. et al., Toxicol In Vitro, (17)497-504 (2003)
- non-patent document 4: Uematsu M. et al., Ophthalmic Research, 39, 308-314, 2007
- non-patent document 5: Masamichi Fukuda et al., Atarashii Ganka (New Ophthalmology) 24(4):521-525, 2007
- 1 cornea
- 2 conjunctiva
- 3 lacrimal fluid reserved in conjunctival-sac
- 4 corneal electrode
- 5 conjunctival electrode
- 6 insulator
- 7 conductor
- 8 electric resistance value measuring device
- 9 conjunctival electrode portion
Claims (12)
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JP2008052567 | 2008-03-03 | ||
JP2008-052567 | 2008-03-03 | ||
JP052567/2008 | 2008-03-03 | ||
PCT/JP2009/053968 WO2009110470A1 (en) | 2008-03-03 | 2009-03-03 | Method of measuring electrical resistance value of corneal trans-epithelium |
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US20110046509A1 US20110046509A1 (en) | 2011-02-24 |
US8478395B2 true US8478395B2 (en) | 2013-07-02 |
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US12/921,069 Expired - Fee Related US8478395B2 (en) | 2008-03-03 | 2009-03-03 | Method of measuring electrical resistance value of corneal trans-epithelium |
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US (1) | US8478395B2 (en) |
EP (1) | EP2248459A4 (en) |
JP (1) | JP5470508B2 (en) |
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ES2372082B1 (en) * | 2010-03-02 | 2013-01-30 | Consejo Superior De Investigaciones Científicas (Csic) | NON INVASIVE SENSOR TO DETERMINE FUNCTIONAL CHARACTERISTICS OF THE CORNEA AND DEVICE INCLUDING SUCH SENSOR. |
MX347468B (en) * | 2012-06-29 | 2017-04-26 | Johnson & Johnson Vision Care | Method and ophthalmic device for galvanic healing of an eye. |
WO2014052393A2 (en) | 2012-09-25 | 2014-04-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods for the diagnosis and treatment of sjögren's syndrome |
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- 2009-03-03 JP JP2010501917A patent/JP5470508B2/en active Active
- 2009-03-03 US US12/921,069 patent/US8478395B2/en not_active Expired - Fee Related
- 2009-03-03 WO PCT/JP2009/053968 patent/WO2009110470A1/en active Application Filing
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JP5470508B2 (en) | 2014-04-16 |
EP2248459A4 (en) | 2014-01-15 |
WO2009110470A1 (en) | 2009-09-11 |
US20110046509A1 (en) | 2011-02-24 |
EP2248459A1 (en) | 2010-11-10 |
JPWO2009110470A1 (en) | 2011-07-14 |
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